Arylisoquinoline alkaloids exhibiting remarkable antiparasitic and/or antiviral properties have recently been identified. Examples of such arylisoquinolines can be found in Boyd et al., U.S. Pat. No. 5,455,251; Boyd et al., U.S. Pat. No. 5,654,432; Frangois et al., U.S. Pat. No. 5,639,761; Francois et al., U.S. patent application Ser. No. 08/843,582; Boyd et al., U.S. Pat. No. 5,409,938; Bringmann et al., U.S. Pat. No. 5,571,919; Bringmann et al., U.S. patent application Ser. No. 08/674,359 U.S. Pat. No. 5,789,594; Bringmann et al., U.S. Pat. No. 5,552,550; U.S. patent application Ser. No. 08/674,362; Bringmann et al., U.S. Pat. No. 5,578,729; Bringmann et al., U.S. patent application Ser. No. 08/721,084 U.S. Pat. No. 5,786,482; and Bringmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, pp. 127-271. Arylisoquinoline alkaloids of this class include monomeric arylisoquinoline alkaloids ("monomers") and dimeric arylisoquinoline alkaloids ("dimers").
Monomeric arylisoquinoline alkaloids include korupensamines and derivatives thereof, which possess a C-8' to C-5 naphthalene/isoquinoline linkage, and non-korupensamines or other monomeric naphthylisoquinoline alkaloids and derivatives thereof, which lack a C-8' to C-5 naphthylene/isoquinoline linkage. The monomeric arylisoquinoline alkaloids and derivatives thereof have particular usefulness as preventative and/or therapeutic agents, for example, as antiparasitic agents. For example, the monomeric arylisoquinoline alkaloid dioncophylline C is among the most potent known antimalarial compounds with in vivo activity against malaria-causing parasites. Further, the monomeric arylisoquinolines can be used as precursors for the synthesis of medically useful dimeric arylisoquinoline alkaloids.
Dimeric arylisoquinoline alkaloids are exemplified by the michellamines, which, based on their molecular structure, are comprised of two monomeric arylisoquinoline alkaloid units coupled together (e.g., two monomeric or molecular "halves"). Michellamines or related arylisoquinoline alkaloid dimers or derivatives thereof may be either "homodimeric" (comprised of two monomeric arylisoquinoline halves which are the same) or "heterodimeric" (comprised of two monomeric arylisoquinoline halves which are different).
Dimeric arylisoquinoline alkaloids have highly desirable and eminently useful medical properties that are distinct from the properties of the monomeric naphthylisoquinoline alkaloids which comprise their molecular halves. For example, the michellamines, such as michellamine B, are highly effective inhibitors of the replication and resultant destructive effects of the human immunodeficiency virus (HIV) in human cells; moreover, the range of anti-HIV activity of these exemplary dimeric arylisoquinoline alkaloids is exceptionally broad, encompassing diverse strains and isolates of both the major viral types, HIV-1 and HIV-2 and a wide variety of human host cell lines; and, their mechanism of antiviral activity is distinct from any other known mechanistic class.
While the available monomeric and dimeric arylisoquinoline alkaloids have a variety of important medical and chemical uses and applications, new derivatives and structural subtypes of this class of compounds are expected to have additional advantageous properties. For example, new monomeric arylisoquinoline alkaloids can serve as precursors or building blocks for new dimeric arylisoquinoline alkaloids. Furthermore, in any given situation or indication, new monomeric and dimeric arylisoquinoline alkaloids are expected to have useful new or improved medical properties and applications, such as greater therapeutic potency against a particular disease or disease-causing organism, a broader spectrum of therapeutic activity against diverse diseases or disease-causing organisms, enhanced oral bioavailability, less toxicity in a particular host mammal, more advantageous pharmacokinetics and/or tissue distribution in a given host mammal, and the like. In addition, new monomeric and dimeric arylisoquinoline alkaloids are potentially useful for in-vitro assays and antimicrobial research.
In view of the foregoing, there exists a need for new medically and chemically useful monomeric and dimeric arylisoquinoline alkaloids and derivatives thereof. The present invention provides such monomeric and dimeric arylisoquinoline alkaloids and derivatives thereof. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.